Abstract Septic shock is a severe condition resulting in a critical reduction of organ perfusion with consequential and common stage 2 and 3 acute kidney injury (AKI) occurring in as many as 60% of patients and with an alarmingly high in-hospital co-morbid mortality rate of up to 70%. Current Surviving Sepsis Guidelines recommend early aggressive fluid resuscitation targeting mean arterial pressure (MAP? 65 mmHg); however aggressive resuscitation commonly results in hypervolemia. Elevated intra-abdominal pressure (IAP), which occurs frequently in critically ill patients, is recognized as a vital parameter reflecting venous outflow that has wide-ranging physiologic effects including an association with AKI. Thus, abdominal perfusion pressure (APP=MAP-IAP) may provide the optimal target to guide hemodynamic support as it reflects both inflow (MAP) and outflow (IAP) perfusion. However, current methods of IAP measurement limit the validation of APP as a hemodynamic target as they are prone to (1) human error, limiting the reproducibility of measurements and (2) contamination resulting in catheter-associated urinary tract infections. Potrero Medical, Inc. has developed the Accuryn Monitoring System, which accurately, automatically and digitally extracts physiological data in real-time from the bladder, without the need for external equipment or manual manipulation. Accuryn received formal 510(k) clearance from the FDA for measurement of IAP, urine output and core temperature in April of 2016. In combination with MAP acquired through standard of care, Accuryn will enable APP-targeted hemodynamic resuscitation in septic shock patients. In this grant, the use of Accuryn to improve clinical outcomes in septic shock patients via both IAP monitoring and APP-targeted hemodynamic resuscitation will be validated. We plan to conduct a 24-month clinical trial with 200 septic shock patients divided among three groups: (1) Monitoring (normal IAP receiving MAP-targeted resuscitation), (2) Standard of Care MAP group (elevated IAP receiving MAP-targeted resuscitation), and (3) APP group (elevated IAP receiving APP? 60 mmHg targeted resuscitation. The primary endpoint for comparison will be incidence or progression (defined by peak severity in creatinine and UO compared to baseline levels) of stage 2 and 3 AKI. Secondary endpoints include ICU- and hospital mortality, frequency and duration of RRT, urinary biomarker data, days on mechanical ventilation, mean duration of vasopressor support, and adverse events. Independent comparisons between these groups will (1) verify that elevated IAP during fluid resuscitation is correlated with AKI in septic shock patients and (2) validate that APP-guided fluid resuscitation reduces the incidence or progression of stage 2 and 3 AKI in septic shock patients compared to MAP-guided resuscitation. With this clinical study, we will validate the need for the Accuryn device to continuously measure IAP and target APP during resuscitation. The data collected from this grant will enable the design of a pivotal phase III clinical study defining APP- targeted hemodynamic support as the new standard of care for septic shock.